Peripheral nerve damage and disease are common health problems that often result in long-term functional deficits. Peripheral axons can regenerate and reinnervate target tissue following nerve injury or disease in young rodent animals. However, human axonal regeneration is very slow, putting both denervated Schwann cells, which provide a permissive microenvironment for regeneration, and target tissues at risk for undergoing atrophy and death, precluding functional recovery. This situation underscores the critical need for agents that can speed up axonal regeneration to restore function. Previously, we have shown that a genetic deletion of BACE1 markedly accelerates axonal regeneration in the injured peripheral nerves of mice. Our studies over the last funding period have focused on deciphering the cellular basis and molecular correlates of this enhanced nerve regeneration in BACE1 KO mice. We have also initiated investigations on the effectiveness of BACE1 inhibitors as potential therapies for nerve disorders. We revealed that BACE1 influences nerve regeneration through infiltrating macrophages and neuron-intrinsic mechanisms. BACE1 inhibitors reproduced the enhanced regeneration phenotype observed in BACE1 KO injured nerves. In this proposal, we plan to expand our research to investigate a causative link between candidate molecules and accelerated nerve regeneration in BACE1 KO mice. Of equal importance, we propose to evaluate whether a clinically applicable pharmacological BACE1 inhibitor accelerates functional and behavioral recovery following a nerve crush injury in mice. To accomplish these goals, we will: 1) use mice with BACE1 conditionally knocked out in macrophages crossed to TNF KO or TNFR1 KO mice (to bypass the perinatal death of the complete double KOs) to investigate whether there is a causative link between increased TNFR1 signaling and augmented macrophage influx; 2) test the hypothesis that a lack of processing of the cell adhesion molecules L1 and CHL1 in BACE1 KO neurons constitutes the neuronal component of accelerated axonal regeneration observed in vivo in BACE1 KO nerves; and 3) determine the efficacy and potency of an experimental Merck BACE1 inhibitor in accelerating functional recovery following a nerve injury using CatWalk, an automated gait analysis system, to evaluate behavioral recovery using a series of tests designed to analyze walking patterns. The results of these studies should provide general insight into the molecular mechanisms of accelerated nerve regeneration in BACE1 KO mice and would test BACE1 inhibitors as a new therapy for nerve trauma and disorders. This is attractive, given that the pharmaceutical industry is actively developing BACE1 inhibitors as candidate therapies for Alzheimer?s disease and is therefore amassing safety, efficacy, and biodistribution data on these molecules. The proposed studies are highly relevant because a faster rate of outgrowth associated with BACE1 inhibition could be useful in enhancing nerve regeneration in human conditions.